Hyperinsulinemia is a key and early feature of diabetes, although, it is not clear if it is pathologic as such because it has not been studied in isolation and methods to reduce it directly have not been pursued. The possibility that hyperinsulinemia at basal glucose (HI) may play a role in disease development needs investigation. The interdependency of HI and insulin resistance makes determining which came first problematic. There are no compelling data that support HI or insulin resistance as the initiating event: both coexist although it is clear that type 2 diabetes (T2D) occurs when ss-cells fail to compensate for insulin resistance. HI is islet-autonomous as it persists for days in isolated islets, indicating that it is not simply a response to stimuli in vivo. Until recently, none of the known pancreatic secretagogues were linked to HI as they depend on glucose metabolism. Therefore, an important gap is the identification of a secretagogue that stimulates in the absence of glucose and with long lasting efficacy. The focus of this application is to identify the mechanism of basal hypersecretion and to determine ways to reverse it. We hypothesize that environmental factors or lipid excess increase the redox state leading to increases in ROS and inhibition of essential ROS regulatory mechanisms, resulting in persistent HI. The following aims will test this concept: 1. What are the mechanisms of increased basal insulin secretion by oleate, mono-oleoyl-glycerol and ROS? 2. What are the protective mechanisms that counteract basal hypersecretion and how do they fail? 3. Can hypersecretion of insulin in vivo be reversed by manipulating redox, ROS or autophagy in vivo or ex vivo? Aims 1 and 2 will identify the pathways involved in basal hypersecretion and Aim 3 will attempt to use the information gained to reverse hypersecretion. We hypothesize that islets from mice fed a high fat diet (HFD) will exhibit increased ROS and impaired autophagy, and normalization of ROS or autophagy will reverse hypersecretion. Completion of the proposed experiments will identify ss-cell alterations that cause hyperinsulinemia, and provide new insights into the consequences of preventing basal hypersecretion on the development of insulin resistance. Support for the ss-cell-mediated insulin resistance hypothesis would lead to radically different strategies for the treatment of insulin resistance and Type 2 diabetes. PUBLIC HEALTH RELEVANCE: Although insulin hypersecretion is the earliest manifestation of beta cell dysfunction associated with obesity and high fat diet, the mechanism behind it and its role in the propagation towards diabetes are still not clear. Completion of the proposed experiments will identify ss-cell alterations that cause hyperinsulinemia, and provide new insights into the consequences of preventing basal hypersecretion on the development of insulin resistance. Support for the role of ss-cell in mediating hyper insulinemia and insulin resistance would lead to radically different strategies for the treatment of insulin resistance and Type 2 diabetes.